One of the biggest challenges that we face in discovering new cancer therapies is that most proteins are considered ?undruggable,? in that most proteins do not possess known binding pockets or ?druggable hotspots? that can be functionally targeted with small-molecules using traditional drug discovery paradigms 1. This grand challenge of tackling the undruggable proteome has catalyzed the explosion of innovative technologies that enable unique access into the functional targeting of biomolecules for drug discovery or new ?druggable modalities.? Examples of some of these small- molecule based technologies include chemoproteomics-enabled covalent ligand screening using activity-based protein profiling (ABPP) and DNA-encoded library platforms for discovering functional or non-functional ligands against undruggable proteins, and proteolysis-targeting chimeras (PROTACs) that use heterobifunctional molecules for recruitment of E3 ligases for targeted ubiquitin-proteasome system-dependent degradation of specific proteins. Each of these approaches facilitate the discovery of small-molecules that access classically intractable cancer targets in a unique manner. While interest in these technologies have exploded in recent years in the pharmaceutical industry, the small- molecule mediated induced proximity modalities (IPMs), such as PROTACs, are just the tip of the iceberg of yet undiscovered IPMs for cancer drug discovery. In my graduate research thus far, I used chemoproteomic approaches to discover that the covalently-acting natural product nimbolide targeted a cysteine within a substrate recognition domain of the E3 ubiquitin ligase RNF114, and that nimbolide could be exploited as a new E3 ligase recruiter for PROTAC applications. In the F99 phase of my proposal, I plan to characterize the broad utility of nimbolide and other fully synthetic RNF114 recruiters for PROTAC applications in the F99 phase of my proposal. In the K00 phase of my proposal, I plan to develop new heterobifunctional IPM paradigms, namely Kinase-Targeting Chimeras (KinaTACs), Phosphatase-Targeting Chimeras (PhosphaTACs), Acetyltransferase-Targeting Chimeras (ATTACs), and Deacetylase-Targeting Chimeras (DATACs) using chemoproteomics-enabled covalent ligand discovery platforms, towards developing new therapeutic modalities for cancer therapy.